RU2627111C2 - Tablet comprising dehydroepiandrosterone (dhea) - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: group of inventions relates to tablet for preventing the loss of testosterone, for maintaining physiological levels of androgens, improving sexual function, mood and health, having a weight of 60-120 mg and consisting of: - 60-100 wt % of granules consisting of: 60-85 wt % of dehydroepiandrosterone (DHEA) granules; 6-35 wt % of microcrystalline cellulose granules; 0-20 wt % of granules of one or more pharmaceutically acceptable granule ingredients; and - 0-40 wt % of one or more pharmaceutically acceptable tablet components, as well as to method of preparing the mentioned tablets.

EFFECT: preparation of small tablets with a high content of DHEA, having acceptable release profile.

18 cl, 10 ex

Description

FIELD OF THE INVENTION

The present invention relates to a tablet that contains human androgen dehydroepiandrosterone (DHEA). More specifically, the invention provides a small tablet having a weight of 30-200 mg, wherein said tablet comprises at least 60% by weight of granules, comprising 50-90% of DHEA by weight of the granules.

The invention also provides a method of manufacturing the aforementioned tablet.

BACKGROUND OF THE INVENTION

Dehydroepiandrosterone (DHEA), also known as 3-beta-hydroxyandrost-5-en-17-one, dehydroisoandrosterone, trans-dehydroandrosterone, Δ ⁵ -androsten-3-β-ol-17-one and prasterone, is of natural origin and is an intermediate product in the synthesis of various steroids from cholesterol. DHEA is the most abundant among human steroid hormones, which produces mainly the adrenal cortex in the form of inactive sulfate ester (DHEA-C). DHEA production also occurs in the testes, ovaries, and brain.

DHEA is credited with a wide range of biological actions in humans and other mammals. It affects androgen receptors both directly and through its metabolites, which include androstandiol and androstenedione, which can then be converted to produce androgen testosterone and estrogen estrone, estradiol and estriol.

DHEA is offered for use in the treatment of many different medical conditions, such as systemic lupus erythematosus, primary adrenal insufficiency, Addison's disease, decreased libido, obesity, osteoporosis, fibromyalgia, and benign gynecological conditions such as endometriosis. It is also suggested that DHEA be used in female hormonal oral contraceptives to prevent loss of testosterone and maintain physiological levels of androgens (WO 2003/041719). The issue of androgen loss, especially testosterone, is a potential problem that every woman taking oral contraceptives experiences.

DHEA can be administered in various ways. Unlike other known androgens, DHEA is active when administered orally. Applicants have found that daily oral administration of DHEA of about 50 mg to a woman taking hormonal oral contraceptives fully normalizes total testosterone and normalizes free testosterone by at least 50% without causing a significant increase in testosterone levels or clinical symptoms of hyperandrogenism, and also without causing increased levels of estradiol. In addition to the ability of DHEA to restore and normalize androgen levels, there are important clinical benefits in several aspects of sexual function (excitability, sensitivity, genital sensations, moisturizing), mood and symptoms of menstrual irregularities.

Thus, it is desirable to include DHEA in, for example, oral contraceptive pills. However, oral contraceptive pills are relatively small and usually weigh approximately 80 mg. The incorporation of approximately 50 mg of DHEA into an 80 mg tablet is a real problem since DHEA inevitably becomes a major component in such a tablet, leaving very little space for other components that are usually found in tablets to make tablets, to dissolve, to prevent retrograde etc.

Oral dosage units containing DHEA are known in US 2005/137178 and describe a method for treating or reducing the risk of hypercholesterolemia, comprising administering a therapeutically effective amount of dehydroepiandrosterone. Oral dosage units containing up to 15 wt.% DHEA are described in the examples in US Patent Application.

Corvi Mora et al. (Development of a sustained-release matrix tablet formulation of DHEA as ternary complex with α-cyclodextrin and glycine, J Incl Phenom Macrocycl Chem (2007) 57, 699-704) describes a sustained release tablet having a weight of 550 mg and containing 25 mg DHEA.

WO 2004/105694 relates to pharmaceutical compositions comprising an active agent; vitamin E substance; surface-active substance. In the examples, the pharmaceutical composition is described as having a total weight of 675 mg and containing 100 mg of DHEA.

WO 2010/145010 is associated with reducing or eliminating the incidence of hot flashes, vasomotor symptoms, and night sweats by administering a combination of (i) a sex steroid precursor such as DHEA, and (ii) a selective estrogen or antiestrogen receptor modulator. Examples of international applications describe a gelatin capsule containing 25 wt.% DHEA.

SUMMARY OF THE INVENTION

Applicants have discovered a method for producing a tablet that is suitable for oral administration of DHEA in a dosage of about 50 mg and which is small enough to be included, in particular, in a conventional blister pack for oral contraceptives.

It has been found that granules with an extremely high DHEA mass can be made by wet granulating a previously prepared mixture of DHEA and microcrystalline cellulose. Moreover, it was found that this granulate can be suitably incorporated into tablets at very high concentrations: 90% by mass or more, thereby enabling the production of tablets having a DHEA concentration of 70% by mass or more.

Accordingly, the present invention provides a tablet that comprises 60-90 wt.% Granulate, which is composed of 50-90 wt.% DHEA, 6-35 wt.% Microcrystalline cellulose and optionally up to 20 wt.% Of one or more pharmaceutically acceptable granulate ingredients . In addition to granules, the tablet may include from 0 to 40 wt.% One or more other pharmaceutically acceptable components of the tablet.

The tablets of the present invention can suitably be used in oral contraceptives to prevent loss of testosterone and to maintain physiological levels of androgens. Other positive clinical effects of these pills include improved sexual function, mood and health.

The invention further provides a process for preparing the aforementioned tablet, and said process comprises the steps of:

- providing a dry pre-cooked mixture of DHEA, microcrystalline cellulose and optionally one or more pharmaceutically acceptable granule ingredients;

- granulating the dry pre-cooked mixture by wetting said pre-prepared mixture with an aqueous solution of a binder;

- drying thus obtained wet granules;

- optionally mixing the dried granules with one or more pharmaceutically acceptable tablet components; and

- pressing the dried granules or a mixture of dried granules and other components of the tablets into tablets.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a tablet having a weight of 30-200 mg, preferably 60-120 mg, and the tablet consists of:

- 60-100 masses. % granules consisting of:

50-90 mass. % granules of dehydrospiandrosterone (DHEA);

6-35 mass. % granules of microcrystalline cellulose;

0-20 mass. % granules of one or more pharmaceutically acceptable granule ingredients; and

0-40 mass. % of one or more other pharmaceutically acceptable tablet components.

The term "DHEA", as used here and above, unless otherwise indicated, refers to dehydroepiandrosterone and its pharmaceutically acceptable esters, including DHEA sulfate.

The term "tablet", as used here and above, refers to a solid composition that is compressed or reduced to a specific form and quantity.

The term "granule", as used here and above, refers to a discrete agglomerate of particles in which the constituent particles are bonded to each other.

The term "microcrystalline cellulose", as used here and above, refers to the non-fibrous form of cellulose, in which the cell wall of the fibers is divided into fragments, usually ranging in size from several hundred microns to several tens of microns in length.

The granules included in the tablet of the present invention typically have a particle size in the range of 25-500 microns. More preferably, the granules have a particle size in the range of 30-350 microns, most preferably in the range of 50-200 microns.

The present invention offers an advantage that allows the manufacture of tablets containing at least 40%, even more preferably at least 50% and most preferably at least 55 mass. % DHEA by weight of the tablet. Typically, the content of DHEA in the tablet does not exceed 85 mass. %, most preferably does not exceed 80 mass. %

The tablet of the present invention preferably comprises 20-120 mg, more preferably 35-80 mg, and most preferably 40-70 mg of DHEA.

The DHEA content of the granules included in the present tablet is preferably in the range of 60-85%, more preferably 65-80% by weight of the granules. Most preferably, the granules contain 75-80% DHEA by weight of the granules.

The amount of microcrystalline cellulose contained in the granules is preferably in the range of 10-25 mass. %

Together DHEA and microcrystalline cellulose preferably comprise at least 85 mass. %, most preferably at least 95% by weight of the granules.

The granules contained in this tablet are agglomerates of DHEA particles and microcrystalline cellulose particles.

It was unexpectedly discovered that DHEA contained in granules favorably affects the processability of these granules. If, for example, DHEA in the granules is replaced with microcrystalline cellulose, the final granules become very heavy and unsuitable for tablet formation.

DHEA, typically found in granules, has a total weighted average particle size in the range of 1-200 μm, more preferably in the range of 10-100 μm.

The microcrystalline cellulose contained in the granules preferably has a total weighted average particle size in the range of 25-200 μm, more preferably in the range of 30-100 μm.

The present invention allows the manufacture of a tablet such that even poorly water soluble DHEA, representing the bulk of the tablet, rapidly dissolves in water. Accordingly, in accordance with the particular advantage of the embodiment, at least 50% of the DHEA contained in the tablet is released within 30 minutes after subjecting it to a dissolution test (USP apparatus II (with a stirring paddle), 900 ml of a solvent of 1% dodecyl sulfate solution sodium in water, 75 rpm, T = 37.5 ° C).

In order to facilitate dissolution, it is preferred that the DHEA-containing granules included in the tablet contain 0.5-20% by weight, preferably 1-10% by weight of a disintegrant. Examples of disintegrants that may be suitable for use include carboxymethyl starch salts, carboxymethyl cellulose salts, starch glycolate salts, and combinations thereof. Most preferably, the disintegrant used in the present tablet is a three-dimensional sodium salt of carboxymethyl cellulose.

The DHEA-containing granules included in the present tablet are suitably produced by wet granulation using an aqueous solution containing a binding agent. Accordingly, the granules preferably comprise 1-12 wt.%, Most preferably 2-8 wt.% A binding agent. Examples of binders that can be suitably used include hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch, and combinations thereof. Most preferably, the binding agent is hydroxypropyl methyl cellulose.

In addition to the granules containing DHEA, the tablet of the present invention preferably comprises 10-40 wt.%, Most preferably 12-25 wt.% Of the excipient.

The filler is preferably selected from lactose, microcrystalline cellulose, maltodextrin, and combinations thereof. According to a particular preferred embodiment, lactose represents at least 50 wt.%, Most preferably at least 70 wt.% Of a filler. The filler used in the tablet preferably has a particle size of 25-200 microns.

One or more pharmaceutically acceptable tablet components that are optionally present in the tablet preferably comprise 0.2-3.0%, most preferably 0.5-1.0%, of a glidant, based on the weight of the tablet. Preferably, said glidant is magnesium stearate.

As described hereinabove and above, the present tablets may suitably be used in oral hormonal contraceptives. Such contraceptives usually contain progestogen and / or estrogen components. Accordingly, the present tablet advantageously contains estrogen and / or progestogen. Estrogen and / or progestogen are preferably administered in a tablet in the form of another granulate, i.e. glanulate other than granules containing DHEA.

In accordance with one preferred embodiment of the invention, the tablet contains another granulate comprising an estrogen selected from ethinyl estradiol, 17β-estradiol, esthetrol and combinations thereof, and said estrogen is contained in the tablet in an amount equivalent to 10-40 μg of ethinyl estradiol (p.o.).

According to another preferred embodiment, the tablet contains another granulate comprising a progestogen, and said progestogen is contained in the tablet in an amount equivalent to 0.05-2.0 mg of levonorgestrel (po).

Another aspect of the present invention relates to a method for producing a tablet as defined hereinabove and above, and said method comprises the steps of:

- providing a dry pre-cooked mixture of DHEA, microcrystalline cellulose and optionally one or more pharmaceutically acceptable granule ingredients;

- granulating the dry pre-cooked mixture by wetting said pre-prepared mixture with an aqueous solution of a binder;

- drying thus obtained wet granules;

- optionally mixing the dried granules with one or more pharmaceutically acceptable tablet components; and

- pressing the dried granules or a mixture of dried granules and other components of the tablets into tablets.

In a preferred embodiment of the present method, the dry pre-cooked mixture comprises:

- 55-92 mass. % DHEA;

- 7-40 mass. % microcrystalline cellulose; and

- 0-40% of one or more other pharmaceutically acceptable granule ingredients.

In the present method, the pre-prepared mixture is preferably moistened in a sufficient amount of an aqueous solution to provide at least 120% water, more preferably 120-300% water, based on the weight of microcrystalline cellulose.

Humidification of the dry pre-prepared mixture can be suitably achieved by, for example, spraying the dry pre-prepared mixture with an aqueous solution of a binder. The wet granulation technique is well known to those skilled in the art of pharmaceuticals.

The aqueous solution preferably contains a binding agent because it helps to form stable agglomerates. Preferably, the aqueous solution contains 1-20 wt.%, Most preferably 3-10 wt.% A binding agent.

The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1

12.5 grams of crude DHEA (Diosynth) with particles between 1 and 50 μm) are transferred to a bowl with high shear forces (MiPro 250, Procept). Then add 7 grams of microcrystalline cellulose (Avicel PH 101, FMC biopolymer, D ₅₀ ± 50 μm) and 0.5 grams of croscarmellose sodium (Ac-di-sol, FMC biopolymer).

A binder solution is prepared containing 10% HPMC (Pharmacoat 603, Harke group) and added to the mixer with high shear at a rate of 0.3 ml / min.

After adding 10 ml of binding solution, the granulation is stopped. Granules that look like snow flakes are dried in an oven at 50 ° C for about 1 hour. The dried granules are manually passed through a 0.5 mm filter. The final granules are free flowing.

0.2 mg of magnesium stearate is added to the granulate to create a pre-compressed mixture. Using a single-impact tablet press equipped with 6 mm round punches, 80 mg tablets are made.

Example 2

Example 1 is repeated except that the amount of DHEA is reduced to 3.5 grams and that granulation is stopped after the addition of 9.3 ml of binding solution. The granulate thus obtained has the appearance of snow flakes. 80 mg tablets can be prepared without difficulty.

Comparative Example A

Example 1 is repeated, except that microcrystalline cellulose is replaced with lactose (Pharmatose 200, DMV-Fonterra) and granulation is stopped after adding 9.4 ml of binding solution.

The dried granules thus obtained are very hard and cannot be passed through a 500 micron filter. Therefore, the material is not used for further processing.

Comparative Example B

20 grams of DHEA are transferred to a high shear mixer (MiPro 250, Procept). A binder solution containing 10% HPMC (3 cP) was prepared and added to the mixer with high shear at a speed of 1 ml / min.

The granulation process becomes very erratic and the mixture becomes waterlogged after adding about 5 ml of binding solution.

The granulate consists of very large balls, and a lot of material sticks to the walls of the bowl. This granulate is not further processed.

Comparative Example C

18 grams of DHEA are transferred to a bowl with high shear (MiPro 250, Procept). 2 grams of gelatinized starch is added and the two components are quickly mixed. Plain water is added to induce granulation. 7.5 ml of water are added before the mixture is granular. A lot of material sticks to the bowl. The granules are dried in a thermostat at 60 ° C.

The obtained granules are very hard and cannot be passed through a 500 micron filter, so this material is not used for further processing.

Comparative Example D

12.5 grams of DHEA are transferred to a bowl with high shear mixers (MiPro 250, Procept). 7 grams of lactose (200 mesh) and 0.5 grams of starch 1500 are added. Normal water is dosed at a rate of 1 ml / min to induce granulation.

After adding 7.5 ml of water to the mixture, granules are not formed. After adding 8.34 ml of water, a solid precipitate forms and a lot of material adheres to the walls of the bowl. This material is not used for further processing.

Comparative Example E

12.5 grams of DHEA are transferred to a bowl with high shear mixers (MiPro 250, Procept). 7 grams of lactose (200 mesh) and 0.5 grams of croscarmellose sodium are added. A binder solution containing 10% HPMC (3 cP) was prepared and added to the mixer with high shear at a speed of 1 ml / min. After adding 7.5 ml of the solution, the granulation appears complete.

Less sediment is formed compared to Example D, but still a lot of material adheres to the walls of the bowl.

The granules are dried in a thermostat at 60 ° C. The obtained granules are very hard and cannot be passed through a 500 micron filter, so this material is not used for further processing.

Comparative Example F

15 grams of microcrystalline cellulose are transferred to a bowl with high shear (MiPro 250, Procept). A binder solution containing 10% HPMC (3 cP) was prepared and added to the mixer with high shear at a speed of 1 ml / min. After adding 9 ml of a binding solution, the granulate looks like snow flakes and some sticking is observed.

After adding 14 ml of water (less than 100 wt.%), A good round precipitate forms.

The precipitate is dried in a thermostat at 60 ° C, and after drying it becomes very hard and has a slight yellow tint.

Example 3

96 grams of DHEA is transferred to a bowl with high shear (MiPro 900, Procept). Then add 21 grams of microcrystalline cellulose and 3 grams of croscarmellose sodium and mix for 1 minute in a mixer with high shear.

A binder solution containing 10% HPMC (3 cP) was prepared and added to the mixer with high shear at a speed of 6 ml / min. Granulation runs very smoothly, the material does not stick to the walls of the bowl, and after adding 63.4 ml of granulating liquid, the granulation is stopped.

The granules are dried in a thermostat at 40 ° C for approximately 12 hours. The dried granules are manually passed through a 0.5 mm filter. The output of the granules is 104 grams.

For compression, 20 grams of lactose are added and mixed for 2 minutes at high shear rate. Add 1 gram of magnesium stearate to this mixture and mix for 30 seconds at high shear rate. Using a single-impact tablet press equipped with 6 mm round punches, 80 mg tablets are made.

The soluble properties of the tablets thus obtained are evaluated using a dissolution test using a USP II apparatus (with a stirring paddle), 900 ml of a solvent of 1% sodium dodecyl sulfate in water, 75 rpm, T = 37.5 ° C) . It was found that after 10 minutes, approximately 73%, and after 20 minutes, approximately 90% of the DHEA contained in the tablet, was released.

Comparative Example G

75 grams of DHEA are transferred to a bowl with high shear (MiPro 900, Procept). Next, 42 grams of lactose 200 mesh and 3 grams of starch 1500 are added and mixed for 1 minute in a mixer with great shear. Water is added at a rate of 6 ml / min. After adding 28.9 ml, the granulate behaves unusually, and the granulation is stopped to clean the material from the walls. Granulation is started anew, but after adding another 4 ml of water, granulation is stopped again to remove a fixed layer from the walls of the bowl. At this stage, the granules are still too dry, so an additional 2.5 ml of water is added. The granulate begins to form large lumps, so the granulation is stopped, and the free contents are transferred to an aluminum plate and dried in a thermostat at 60 ° C for 2 hours. Get 85 grams of very hard granules.

The granulate is manually passed through a 0.5 mm filter and mixed with 0.9 grams of magnesium stearate. Tablets with a diameter of 6 mm and tablets weighing 80 mg are made using a single-impact tablet press.

The soluble properties of the tablets thus obtained were evaluated in the same manner as in Example 3. It was found that even after 60 minutes, no more than 4% of the DHEA contained in the tablet was released.

Claims (28)

1. A tablet to prevent the loss of testosterone, to maintain physiological levels of androgens, improve sexual function, mood and health, having a mass of 60-120 mg, and this tablet consists of: - 60-100 wt.% Granules, consisting of: 60-85% by weight of dehydroepiandrosterone (DHEA) granules; 6-35% by weight of microcrystalline cellulose granules; 0-20% by weight of the granules of one or more pharmaceutically acceptable granule ingredients; and - 0-40 wt.% One or more other pharmaceutically acceptable components of the tablets. 2. The tablet according to claim 1, where the granules have a particle size in the range of 25-500 microns. 3. The tablet according to claim 1 or 2, where the tablet includes at least 40% DHEA by weight of the tablet. 4. The tablet according to claim 3, where the tablet includes at least 50% DHEA by weight of the tablet 5. The tablet according to claim 1 or 2, where DHEA contained in the granules has a total weighted average particle size in the range of 1-200 μm. 6. The tablet according to claim 1 or 2, where the granules include 10-25 wt.% Microcrystalline cellulose. 7. The tablet according to claim 1 or 2, where microcrystalline cellulose has a total weighted average particle size in the range of 25-200 microns. 8. The tablet according to claim 1, where the granules include 0.5-20 wt.% Disintegrant. 9. The tablet of claim 8, where the granules include 1-10 wt.% Disintegrant. 10. The tablet of claim 8 or 9, where the disintegrant is selected from a carboxymethyl starch salt, a carboxymethyl cellulose salt, a starch glycolate salt, and combinations thereof. 11. The tablet according to claim 1, where the granules include 1-12 wt.% A binding agent. 12. The tablet according to claim 11, where the granules include 2-8 wt.% A binding agent. 13. The tablet according to claim 11 or 12, where the binding agent is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch, and combinations thereof. 14. The tablet according to claim 1, where one or more pharmaceutically acceptable components of the tablet include 10-40% of the excipient by weight of the tablet. 15. The tablet according to 14, where one or more pharmaceutically acceptable components of the tablet include 12-25% of the excipient by weight of the tablet. 16. The tablet of claim 14 or 15, wherein the excipient is selected from lactose, microcrystalline cellulose, maltodextrin, and combinations thereof. 17. The tablet according to claim 1 or 2, where the tablet contains another granulate, including a progestogen, and said progestogen is contained in the tablet in an amount equivalent to 0.05-2.0 mg of levonorgestrel (r.o.). 18. A method of producing a tablet according to any one of the preceding paragraphs, comprising the steps of: - providing a dry pre-prepared mixture of DHEA, microcrystalline cellulose and optionally one or more other pharmaceutically acceptable granule ingredients; - granulating the dry pre-cooked mixture by wetting said pre-prepared mixture with an aqueous solution of a binder; - drying thus obtained wet granules; - optionally mixing the dried granules with one or more other pharmaceutically acceptable tablet components; and - pressing the dried granules or a mixture of dried granules and other components of the tablet into tablets.